Our objective is to determine the long-term sequelae of the administration of morphine and other drugs of abuse to rodent parents, prior to mating, upon the development of subsequent progeny. Previous studies have demonstrated that this pregestational administration of opioids to male or female rodents results in behavioral deficits among first generation offspring and a retardation in growth of the four generations of progeny observed to date. The major objectives of this proposal are to elucidate the mechanism(s) of this pregestational influence, determine its specificity for narcotic analgesics and assess the nature and extent of the deficits produced . The possibility that genetic factors may be involved in the pregestational phenomenon and that pregestational opioids may lead to an altered response to stress among subsequent progeny will be addressed. To further explore the possibility of genetic influences, an extensive series of selective inbreeding studies will be conducted. Resultant progeny will be evaluated by the utilization of developmental, behavioral and neuroendocrine procedures which are capable of discriminating groups of offspring from control and treated parentage. These procedures will also serve to explore the possibility that an altered responsiveness to stress may underly the behavioral deficits. To examine the opioid specificity of the pregestational influence, the effect on subsequent progeny of the pregestational administration of opioid agonists inactive stereoisomers and antagonist will be compared. The participation of withdrawal and dose-related factors will be systematically assessed. Cross-fostering procedures will be employed to evaluate the role of pre-and postnatal influences.